Glycopeptide disulfide and thioester derivatives

ABSTRACT

Disclosed are disulfide and thioester derivatives of glycopeptides and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.

PRIORITY OF INVENTION

This application claims priority to U.S. Provisional Application No.60/213,146, filed Jun. 22, 2000, which application is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to novel disulfide and thioester derivativesof glycopeptide antibiotics and related compounds. This invention isalso directed to pharmaceutical compositions containing suchglycopeptide derivatives, methods of using such glycopeptide derivativesas antibacterial agents, and processes and intermediates useful forpreparing such glycopeptide derivatives.

2. Background

Glycopeptides are a well-known class of antibiotics produced by variousmicroorganisms (see Glycopeptide Antibiotics, edited by R. Nagarajan,Marcel Dekker, Inc. New York (1994)). These complex multi-ring peptidecompounds are very effective antibacterial agents against a majority ofGram-positive bacteria. Although potent antibacterial agents, theglycopeptides antibiotics are not used in the treatment of bacterialdiseases as often as other classes of antibiotics, such as thesemi-synthetic penicillins, cephalosporins and lincomycins, due toconcerns regarding toxicity.

In recent years, however, bacterial resistance to many of thecommonly-used antibiotics has developed (see J. E. Geraci et al., MayoClin. Proc. 1983, 58, 88-91; and M. Foldes, J. Antimicrob. Chemother.1983, 11, 21-26). Since glycopeptide antibiotics are often effectiveagainst these resistant strains of bacteria, glycopeptides such asvancomycin have become the drugs of last resort for treating infectionscaused by these organisms. Recently, however, resistance to vancomycinhas appeared in various microorganisms, such as vancomycin-resistantenterococci (VRE), leading to increasing concerns about the ability toeffectively treat bacterial infections in the future (see HospitalInfection Control Practices Advisory Committee, Infection ControlHospital Epidemiology, 1995, 17, 364-369; A. P. Johnson et al., ClinicalMicrobiology Rev., 1990, 3, 280-291; G. M. Eliopoulos, European J.Clinical Microbiol., Infection Disease, 1993, 12, 409-412; and P.Courvalin, Antimicrob. Agents Chemother, 1990, 34, 2291-2296).

A number of derivatives of vancomycin and other glycopeptides are knownin the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987;4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Otherderivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353;WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer.Chem. Soc., 1996, 118, 13107-13108; J. Amer. Chem. Soc., 1997, 119,12041-12047; and J. Amer. Chem. Soc., 1994, 116, 4573-4590.

Despite the above referenced disclosures, a need currently exists fornovel glycopeptide derivatives having effective antibacterial activityand an improved mammalian safety profile. In particular, a need existsfor glycopeptide derivatives which are effective against a wide spectrumof pathogenic microorganism, including vancomycin-resistantmicroorganisms, and which have reduced tissue accumulation and/ornephrotoxicity.

SUMMARY OF THE INVENTION

The present invention provides novel disulfide and thioesterglycopeptide derivatives having highly effective antibacterial activityand an improved mammalian safety profile. More specifically, thedisulfide and thioester glycopeptide derivatives of the inventionunexpectedly exhibit reduced tissue accumulation and/or nephrotoxicitywhen administered to a mammal.

Accordingly, the invention provides a compound of the invention, whichis a glycopeptide compound having at least one substituent of theformula:—R^(a)—Y—R^(b)—(Z)_(X)wherein

-   -   each R^(a) is independently alkylene, substituted alkylene,        alkenylene, substituted alkenylene, alkynylene, substituted        alkynylene, cycloalkylene, substituted cycloalkylene,        cycloalkenylene, substituted cycloalkenylene, arylene,        heteroarylene, heterocyclene, —C(O)-alkylene, substituted        —C(O)-alkylene, —C(O)-alkenylene, substituted —C(O)-alkenylene,        —C(O)-alkynylene, substituted —C(O)-alkynylene,        —C(O)-cycloalkylene, substituted —C(O)-cycloalkylene,        —C(O)-cycloalkenylene, substituted —C(O)-cycloalkenylene,        —C(O)-arylene, —C(O)-heteroarylene, or —C(O)-heterocyclene;    -   each R^(b) is independently a covalent bond, alkylene,        substituted alkylene, alkenylene, substituted alkenylene,        alkynylene, substituted alkynylene, cycloalkylene, substituted        cycloalkylene, cycloalkenylene, or substituted cycloalkenylene;        provided R^(b) is not a covalent bond when Z is hydrogen;    -   each Y is independently selected from the group consisting of        oxygen, sulfur, —S—S—, —S—C(═O)—, —C(═O)—S—, —NR^(c)—, —S(O)—,        —SO₂—, —NR^(c)C(O)—, —OSO₂—, —OC(O)—, —NR^(c)SO₂—, —C(O)NR^(c)—,        —C(O)O—, —SO₂NR^(c)—, —SO₂O—, —P(O)(OR^(c))O—,        —P(O)(OR^(c))NR^(c)—, —OP(O)(OR^(c))O—, —OP(O)(OR^(c))NR^(c)—,        —OC(O)O—, —NR^(c)C(O)O—, —NR^(c)C(O)NR^(c)—, —OC(O)NR^(c)—,        C(═O), and —NR^(c)SO₂NR^(c)—;    -   each Z is independently selected from hydrogen, aryl,        cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;    -   each R^(c) is independently selected from the group consisting        of hydrogen, alkyl, substituted alkyl, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl, heterocyclic and —C(O)R^(d);    -   each R^(d) is independently selected from the group consisting        of alkyl, substituted alkyl, alkenyl, substituted alkenyl,        alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl and heterocyclic;    -   x is 1 or 2;    -   or a pharmaceutically acceptable salt, stereoisomer, or prodrug        thereof,    -   provided that at least one Y is —S—S—, —S—C(═O)—, or —C(═O)—S—.

Preferably, each R^(a) is independently selected from the groupconsisting of alkylene, substituted alkylene, alkenylene, substitutedalkenylene, alkynylene and substituted alkynylene.

Preferably, each R^(b) is independently selected from the groupconsisting of a covalent bond, alkylene, substituted alkylene,alkenylene, substituted alkenylene, alkynylene and substitutedalkynylene, provided R^(b) is not a covalent bond when Z is hydrogen.

Preferred compounds of the invention exclude glycopeptides substitutedat the carboxy terminus with a substituent that comprises more than onecarboxy group.

A preferred compound of the invention is a glycopeptide of formula I:

wherein:

-   -   R¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl, heterocyclic, —R^(a)—Y—R^(b)—(Z)_(x); or a        saccharide group optionally substituted with        —R^(a)—Y—R^(b)—(Z)_(x);    -   R² is hydrogen or a saccharide group optionally substituted with        —R^(a)—Y—R^(b)—(Z)_(x), R^(f), —C(O)R^(f), or        —C(O)—R^(a)—Y—R^(b)—(Z)_(x);    -   R³ is —OR^(c), —NR^(c)R^(c), —O—R^(a)—Y—R^(b)—(Z)_(x),        —NR^(c)—R^(a)—Y—R^(b)—(Z)_(x), —NR^(c)R^(e), or —O—R^(e);    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, —R^(a)—Y—R^(b)—(Z)_(x), —C(O)R^(d) and a        saccharide group optionally substituted with        —R^(a)—Y—R^(b)—(Z)_(x), R^(f), —C(O)R^(f), or        —C(O)—R^(a)—Y—R^(b)—(Z)_(x);    -   R⁵ is selected from the group consisting of hydrogen, halo,        —CH(R^(c))—NR^(c)R^(c), —CH(R^(c))—NR^(c)R^(e),        —CH(R^(c))—NR^(c)—R^(a)—Y—R^(b)—(Z)_(x), —CH(R^(c))—R^(x), and        —CH(R^(c))—NR^(c)—R^(a)—C(═O)—R^(x);    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, —R^(a)—Y—R^(b)—(Z)_(x), —C(O)R^(d) and a        saccharide group optionally substituted with        —NR^(c)—R^(a)—Y—R^(b)—(Z)_(x), or R⁵ and R⁶ can be joined,        together with the atoms to which they are attached, form a        heterocyclic ring optionally substituted with        —NR^(c)—R^(a)—Y—R^(b)—(Z)_(x);    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl,—R^(a)—Y—R^(b)—(Z)_(x), and —C(O)R^(d);    -   R⁸ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl, substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and        heterocyclic;    -   R⁹ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl, substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and        heterocyclic;    -   R¹⁰ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl, substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and        heterocyclic; or R⁸ and R¹⁰ are joined to form —Ar¹—O—Ar²—,        where Ar¹ and Ar² are independently arylene or heteroarylene;    -   R¹¹ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl, substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and        heterocyclic, or R¹⁰ and R¹¹ are joined, together with the        carbon and nitrogen atoms to which they are attached, to form a        heterocyclic ring;    -   R¹² is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl, substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,        heterocyclic, —C(O)R^(d), —C(NH)R^(d), —C(O)NR^(c)R^(c),        —C(O)OR^(d), —C(NH)NR^(c)R^(c) and —R^(a)—Y—R^(b)—(Z)_(x), or        R¹¹ and R¹² are joined, together with the nitrogen atom to which        they are attached, to form a heterocyclic ring;    -   R¹³ is selected from the group consisting of hydrogen or —OR¹⁴;    -   R¹⁴ is selected from hydrogen, —C(O)R^(d) and a saccharide        group;    -   each R^(a) is independently selected from the group consisting        of alkylene, substituted alkylene, alkenylene, substituted        alkenylene, alkynylene and substituted alkynylene;    -   each R^(b) is independently selected from the group consisting        of a covalent bond, alkylene, substituted alkylene, alkenylene,        substituted alkenylene, alkynylene and substituted alkynylene,        provided R^(b) is not a covalent bond when Z is hydrogen;    -   each R^(c) is independently selected from the group consisting        of hydrogen, alkyl, substituted alkyl, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl, heterocyclic and —C(O)R^(d);    -   each R^(d) is independently selected from the group consisting        of alkyl, substituted alkyl, alkenyl, substituted alkenyl,        alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl and heterocyclic;    -   R^(e) is a saccharide group;    -   each R^(f) is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,        substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,        aryl, heteroaryl, or heterocyclic;    -   R^(x) is a nitrogen-linked amino saccharide or a nitrogen-linked        heterocycle;    -   X¹, X² and X³ are independently selected from hydrogen or        chloro;    -   each Y is independently selected from the group consisting of        oxygen, sulfur, —S—S—, —S—C(═O)—, —C(═O)—S—, —NR^(c)—, —S(O)—,        —SO₂—, —NR^(c)C(O)—, —OSO₂—, —OC(O)—, —NR^(c)SO₂—, —C(O)NR^(c)—,        —C(O)O—, —SO₂NR^(c)—, —SO₂O—, —P(O)(OR^(c))O—,        —P(O)(OR^(c))NR^(c)—, —OP(O)(OR^(c))O—, —OP(O)(OR^(c))NR^(c)—,        —OC(O)O—, —NR^(c)C(O)O—, —NR^(c)C(O)NR^(c)—, —OC(O)NR^(c)—,        C(═O), and —NR^(c)SO₂NR^(c)—;    -   each Z is independently selected from hydrogen, aryl,        cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;    -   n is 0, 1 or 2; and    -   x is 1 or 2;    -   or a pharmaceutically acceptable salt, stereoisomer, or prodrug        thereof;    -   wherein the glycopeptide is substituted with one or more groups        wherein Y is —S—S—, —S—C(═O)—, or —C(═O)—S—;    -   provided R³ is not a substituent that comprises more that one        carboxy group; and    -   provided R³ is not a substituent that comprises one or more        saccharide groups and a carboxy group; and    -   provided R¹ is not an amino saccharide wherein the        saccharide-amine is substituted with a substituent that        comprises two or more hydroxy groups.

Preferably, R¹ is an amino saccharide wherein the saccharide-amine issubstituted with: —CH₂CH₂—NH—(CH₂)₉CH₃; —CH₂CH₂CH₂—NH—(CH₂)₈CH₃;—CH₂CH₂CH₂CH₂—NH—(CH₂)₇CH₃; —CH₂CH₂—NHSO₂—(CH₂)₉CH₃;—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃; —CH₂CH₂—S—(CH₂)₈CH₃; —CH₂CH₂—S—(CH₂)₉CH₃;—CH₂CH₂—S—(CH₂)₁₀CH₃; —CH₂CH₂CH₂—S—(CH₂)₈CH₃; —CH₂CH₂CH₂—S—(CH₂)₉CH₃;—CH₂CH₂CH₂—S—(CH₂)₃—CH═CH—(CH₂)₄CH₃ (trans); —CH₂CH₂CH₂CH₂—S—(CH₂)₇CH₃;—CH₂CH₂—S(O)—(CH₂)₉CH₃; —CH₂CH₂—S—(CH₂)₆Ph; —CH₂CH₂—S—(CH₂)₈Ph;—CH₂CH₂CH₂—S—(CH₂)₈Ph; —CH₂CH₂—NH—CH₂₋₄-(4—Cl—Ph)—Ph;—CH₂CH₂—NH—CH₂-4-[4-(CH₃)₂CHCH₂—]—Ph; —CH₂CH₂—NH—CH₂-4(4-CF₃—Ph)—Ph;—CH₂CH₂—S—CH₂-4-(4-Cl—Ph)—Ph; —CH₂CH₂—S(O)—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—S—CH₂-4-(4-Cl—Ph)—Ph; —CH₂CH₂CH₂—S(O)—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—S—CH₂-4-[3,4-di-Cl—PhCH₂O—)—Ph;—CH₂CH₂—NHSO₂—CH₂-4-[4-(4-Ph)—Ph]—Ph;—CH₂CH₂CH₂—NHSO₂—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—NHSO₂—CH₂-4-(Ph—C≡C—)—Ph; —CH₂CH₂CH₂—NHSO₂-4-(4-Cl—Ph)—Ph; or—CH₂CH₂CH₂—NHSO₂-4-(naphth-2-yl)-Ph. More preferably, the alkylatedglycopeptide product is also compound of formula I wherein R¹ is anamino saccharide wherein the saccharide-amine is substituted with4-(4-chlorophenyl)benzyl or 4-(4-chlorobenzyloxy)benzyl.

More preferably, R¹ is an amino containing saccharide group substitutedon the amine with a substituent that comprises one or more (e.g. 1, 2,or 3) disulfide (—S—S—) or thioester (—S—C(═O)— bonds.

More preferably, R¹ is an amino containing saccharide group substitutedon the amine with a group of formula —R^(a)—W—R^(h) wherein: W is —S—S—or —S—C(═O)— and R^(h) is alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, orheterocyclic.

More preferably, R^(a)is alkylene, substituted alkylene, alkenylene,substituted alkenylene, alkynylene, substituted alkynylene,—C(O)-alkylene, substituted —C(O)-alkylene, —C(O)-alkenylene,substituted —C(O)-alkenylene, —C(O)-alkynylene, or substituted—C(O)-alkynylene.

More preferably, R^(b) is alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, or substituted alkynyl.

For example, R¹ is preferably a saccharide group of the formula (III):

wherein R¹⁵ is —R^(a)—W—R^(h); and R¹⁶ is hydrogen or methyl.

Preferably, R² is hydrogen.

In a preferred embodiment, R³ is —R^(a)—W—R^(h) where R^(a), R^(h), andW are as defined herein. In another preferred embodiment, R³ is —OR^(c)or —NR^(c)R^(c); more preferably R³ is —OH.

Preferably, R³ is —OH; —NH—(CH₂)₃—N(CH₃)₂; N-(D-glucosamine);—NHCH(CO₂CH₃)CH₂CO₂CH₃; —NH(CH₂)₃-(morpholin-4-yl);—NH(CH₂)₃—NH(CH₂)₂CH₃;—NH(CH₂-piperidin-1-yl; —NH(CH₂)₄NHC(N)NH₂;—NH(CH₂)₂—N⁺(CH₃) ₃; —NHCH(COOH)(CH₂)₃NHC(N)NH₂; —NH—[(CH₂)₃—NH—]₃—H;—N[(CH₂)₃N(CH₃)₂]₂; —NH(CH₂)₃-imidazol-1-yl; —NHCH₂-4-pyridyl;—NH(CH₂)₃CH₃; —NH(CH₂)₂OH; —NH(CH₂)₅OH; —NH(CH₂)₂OCH₃;—NHCH₂-tetrahydrofuran-2-yl; —N[(CH₂) ₂OH]₂; —NH(CH₂)₂N[(CH₂)₂OH]₂;—NHCH₂COOH; —NHCH(COOH)CH₂OH; —NH(CH₂)₂COOH; N-(glucamine);—NH(CH₂)₂COOH; —NH(CH₂)₃SO₃H; —NHCH(COOH)(CH₂)₂NH₂;—NHCH(COOH)(CH₂)₃NH₂; —NHCH(COOH)CH₂CO₂(CH₂)₃—N⁺(CH₃)₃;—NHCH(COOH)CH₂CO₂(CH₂) ₂C(O)—N(CH₃)₂;—NHCH(COOH)CH₂CO₂(CH₂)₃-morpholin-4-yl;—NHCH(COOH)CH₂CO₂(CH₂)₂OC(O)C(CH₃)₃; —NHCH(CH₂COOH)CO₂(CH₂)₃—N⁺(CH₃)₃;—NHCH(CH₂COOH)CO₂(CH₂)₂C(O)N(CH₃)₂;—NHCH(CH₂COOH)CO₂(CH₂)₃-morpholin-4-yl;—NHCH(CH₂COOH)CO₂(CH₂)₂OC(O)C(CH₃)₃; —NHCH(COOH)CH₂CO₂CH₃;—NHCH(CH₂COOH)CO₂(CH₂)₂N(CH₃)₂; —NHCH(COOH)CH₂CO₂CH₂C(O)N(CH₃)₂;—NHCH(CH₂COOH)CO₂CH₂C(O)N(CH₃)₂; —NHCH(CH₂COOH)CO₂CH₃; —NH(CH₂)₃N(CH₃)₂;—NHCH₂CH₂CO₂CH₃; —NHCH[CH₂CO₂CH₂C(O)N(CH₃)₂]—CO₂CH₂—C(O)—N(CH₃)₂;—NHCH₂CO₂CH₃; —N-(methyl 3-amino-3-deoxyaminopyranoside); —N-(methyl3-amino-2,3,6-trideoxyhexopyranoside);—N-(2-amino-2-deoxy-6-(dihydrogenphosphate)-glucopyranose;—N-(2-amino-2-deoxygluconic acid); —NH(CH₂)₄COOH; —N—(N—CH₃—D-glucamine;—NH(CH₂)₆COOH; —O(D-glucose); —NH(CH₂)₃OC(O)CH(NH₂)CH₃;—NH(CH₂)₄CH(C(O)-2-HOOC-pyrrolidin-1-yl)NHCH(COOH)—CH₂CH₂Ph (S,Sisomer); —NH—CH₂CH₂—NH—(CH₂)₉CH₃; —NH(CH₂)C(O)CH₂C(O)N(CH₃)₂;

Preferably, R⁴, R⁶ and R⁷ are each independently selected from hydrogenor —C(O)R^(d). More preferably, R⁴, R⁶ and R⁷ are each hydrogen.

In a preferred embodiment, R⁵ is —R^(a)—W—R^(h) where R^(a), R^(h), andW are as defined herein. In another preferred embodiment, R⁵ ishydrogen, —CH₂—NHR^(c), —CH₂—NR^(c)R^(e) or—CH₂—NH—R^(a)—Y—R^(b)—(Z)_(x). R⁵ can also preferably be hydrogen;—CH₂—N—(N—CH₃—D-glucamine); —CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—NHC(O)—(CH₂)₃COOH; —CH₂—NH—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—COOH;—CH₂—NH—(CH₂)₅COOH; —CH₂-(morpholin-4-yl); —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH;—CH₂—NH—CH₂CH(OH)—CH₂OH; —CH₂—N[CH₂CH₂OH]₂; —CH₂—NH—(CH₂)₃—N(CH₃)₂;—CH₂—N[(CH₂)₃—N(CH₃)₂]₂; —CH₂—NH—(CH₂)₃-(imidazol-1-yl); —CH₂—NH—(CH₂₃-(morpholin-4-yl); —CH₂—NH—(CH₂)₄—NHC(NH)NH₂;—CH₂—N-(2-amino-2-deoxygluconic acid);—CH₂—NH—CH₂CH₂—NH—(CH₂)₁₁CH₃;—CH₂—NH—CH(COOH)CH₂COOH; —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₇CH₃;—CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₈CH₃; —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃; —CH₂—NH—CH₂CH₂—NH—(CH₂)₇CH₃;—CH₂—NH—CH₂CH₂—O—CH₂CH₂OH; —CH₂—NH—CH₂CH₂C(O)—N-(D-glucosamine);—CH₂—NH-(6-oxo-[1,3]oxazinan-3-yl); —CH₂—NH—CH₂CH₂—S—(CH₂) ₇CH₃;—CH₂—NH—CH₂CH₂—S—(CH₂)₈CH₃; —CH₂—NH—CH₂CH₂—S—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—S—(CH₂)₁₁CH₃; —CH₂—NH—CH₂CH₂—S—(CH₂)₆Ph;—CH₂—NH—CH₂CH₂—S—(CH₂)₈Ph; —CH₂—NH—CH₂CH₂—S—(CH₂)₁₀Ph;—CH₂—NH—CH₂CH₂—S—CH₂-(4-(4-CF₃-Ph)Ph); —CH₂—NH—CH₂CH₂—NH—(CH₂)₁₁CH₃; or—CH₂—NH—(CH₂)₅—COOH.

Preferably, R⁸ is —CH₂C(O)NH₂, —CH₂COOH, benzyl, 4-hydroxyphenyl or3-chloro-4-hydroxyphenyl.

Preferably, R⁹ is hydrogen or alkyl.

Preferably, R¹⁰ is alkyl or substituted alkyl. More preferably, R¹⁰ isthe side-chain of a naturally occurring amino acid, such as isobutyl.

Preferably, R¹¹ is hydrogen or alkyl.

Preferably, R¹² is hydrogen, alkyl, substituted alkyl or —C(O)R^(d). R¹²can also preferably be hydrogen; —CH₂COOH; —CH₂—[CH(OH)]₅CH₂OH;—CH₂CH(OH)CH₂OH; —CH₂CH₂NH₂; —CH₂C(O)OCH₂CH₃; —CH₂-(2-pyridyl);—CH₂—[CH(OH)]₄COOH; —CH₂-(3-carboxyphenyl); (R)—C(O)CH(NH₂)(CH₂)₄NH₂;—C(O)Ph; —C(O)CH₂NHC(O)CH₃; E—CH₂CH₂—S—(CH₂)₃CH═CH(CH₂)₄CH₃; or—C(O)CH₃.

Preferably, X¹ and X² are each chloro.

Preferably, X³ is hydrogen.

Preferably, each Y is independently selected from the group consistingof oxygen, sulfur, —S—S—, —S—C(═O)—, —C(═O)—S—, —NR^(c)—, —S(O)—, —SO₂—,—NR^(c)C(O)—, —OSO₂—, —OC(O)—, —NR^(c)SO₂—, —C(O)NR^(c)—, —C(O)O—,—SO₂NR^(c)—, —SO₂O—, —P(O)(OR^(c))O—, —P(O)(OR^(c))NR^(c)—,—OP(O)(OR^(c))O—, —OP(O)(OR^(c))NR^(c)—, —OC(O)O—, —NR^(c)C(O)O—,—NR^(c)C(O)NR^(c)—, —OC(O)NR^(c)—, and —NR^(c)SO₂NR^(c)—;

Preferably, n is 0 or 1, and more preferably, n is 1.

A preferred compound of the invention is a glycopeptide of formula II:

wherein:

-   -   R¹⁹ is hydrogen;    -   R²⁰ is —R^(a)—W—R^(h)    -   R¹ is independently alkylene, substituted alkylene, alkenylene,        substituted alkenylene, alkynylene, substituted alkynylene,        cycloalkylene, substituted cycloalkylene, cycloalkenylene,        substituted cycloalkenylene, arylene, heteroarylene,        heterocyclene, —C(O)-alkylene, substituted —C(O)-alkylene,        —C(O)-alkenylene, substituted —C(O)-alkenylene,        —C(O)-alkynylene, substituted —C(O)-alkynylene,        —C(O)-cycloalkylene, substituted —C(O)-cycloalkylene,        —C(O)-cycloalkenylene, substituted —C(O)-cycloalkenylene,        —C(O)-arylene, —C(O)-heteroarylene, or —C(O)-heterocyclene;    -   R^(h) is alkyl, substituted alkyl, alkenyl, substituted alkenyl,        alkynyl, substituted alkynyl, cycloalkyl, substituted        cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,        heteroaryl, or heterocyclic;    -   Y is —S—S—, —C(═O)S—, or —S—C(═O)— and    -   R³, and R⁵ have any of the values or preferred values described        herein;    -   or a pharmaceutically acceptable salt, stereoisomer, or prodrug        thereof;    -   provided R³ is not a substituent that comprises more than one        carboxy group; and    -   provided R³ is not a substituent that comprises one or more        saccharide groups and a carboxy group; and    -   provided R²⁰ is not a substituent that comprises two or more        hydroxy groups.

More preferably, for a compound of formula II, R^(a) is alkylene,substituted alkylene, alkenylene, substituted alkenylene, alkynylene,substituted alkynylene, —C(O)-alkylene, substituted —C(O)-alkylene,—C(O)-alkenylene, substituted —C(O)-alkenylene, —C(O)-alkynylene, orsubstituted —C(O)-alkynylene; and R^(h) is alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.

A preferred value for R¹⁵, R²⁰, or —R^(a)—Y—R^(b)—(Z)_(x) is—CH₂CH₂—NH—(CH₂)₉CH₃; —CH₂CH₂CH₂—NH—(CH₂)₈CH₃;—CH₂CH₂CH₂CH₂—NH—(CH₂)₇CH₃; —CH₂CH₂—NHSO₂—(CH₂)₉CH₃;—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃; —CH₂CH₂—S—(CH₂)₈CH₃; —CH₂CH₂—S—(CH₂)₉CH₃;—CH₂CH₂—S—(CH₂)₁₀CH₃; —CH₂CH₂CH₂—S—(CH₂)₈CH₃; —CH₂CH₂CH₂—S—(CH₂)₉CH₃;—CH₂CH₂CH₂—S—(CH₂)₃—CH═CH—(CH₂)₄CH₃(trans); —CH₂CH₂CH₂CH₂—S—(CH₂)₇CH₃;—CH₂CH₂—S(O)—(CH₂)₉CH₃; —CH₂CH₂—S—(CH₂)₆Ph; —CH₂CH₂—S—(CH₂)₈Ph;—CH₂CH₂CH₂—S—(CH₂)₈Ph; —CH₂CH₂—NH—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂—NH—CH₂-4-[4-(CH₃)₂CHCH₂—]—Ph; —CH₂CH₂—NH—CH₂-4-(4-CF₃—Ph)—Ph;—CH₂CH₂—S—CH₂-4-(4-Cl—Ph)—Ph; —CH₂CH₂—S(O)—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—S—CH₂-4-(4-Cl—Ph)—Ph; —CH₂CH₂CH₂—S(O)—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—S—CH₂-4-[3,4-di-Cl—PhCH₂O—)—Ph;—CH₂CH₂—NHSO₂—CH₂-4-[4-(4-Ph)—Ph]—Ph;—CH₂CH₂CH₂—NHSO₂—CH₂-4-(4-Cl—Ph)—Ph;—CH₂CH₂CH₂—NHSO₂—CH₂-4-(Ph—C≡C—)—Ph; —CH₂CH₂CH₂—NHSO₂-4-(4-Cl—Ph)—Ph; or—CH₂CH₂CH₂—NHSO₂-4-(naphth-2-yl)-Ph. Another preferred value for R¹⁵ orR²⁰ 4-(4-chlorophenyl)benzyl or 4-(4-chlorobenzyloxy)benzyl

The invention also provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of the invention. In one preferred embodiment, thepharmaceutically acceptable carrier comprises an aqueous cyclodextrinsolution. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrinor sulfobutyl ether β-cyclodextrin. More preferably, the cyclodextrin ishydroxypropyl-β-cyclodextrin.

The compounds of the invention are highly effective antibacterialagents. Accordingly, the invention also provides a method of treating amammal having a bacterial disease, comprising administering to themammal a therapeutically effective amount of a compound of theinvention. The invention also provides a method of treating a mammalhaving a bacterial disease, comprising administering to the mammal atherapeutically effective amount of a pharmaceutical composition of theinvention.

The invention also provides processes and intermediates useful forpreparing compounds of the invention, which processes and intermediatesare described further herein.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a bacterial disease in a mammal.

Preferred compounds of the invention are the compounds of formula IIshown in Table I below wherein R¹⁹ is hydrogen.

TABLE I Preferred Compounds of formula II Compound R³ R⁵ R²⁰ 1 OH H—(CH₂)₂S—S(CH₂)₇CH₃ 2 OH H —(CH₂)₃S—S(CH₂)₇CH₃ 3 OH H—(CH₂)₂S—S(CH₂)₈CH₃ 4 OH H —(CH₂)₃S—S(CH₂)₈CH₃

Another preferred group of compounds of the invention are disulfide andthioester derivatives of the glycopeptide antibiotic A82846B (also knownas chloroorienticin A oy LY264826). See for example R. Nagarajan et al.,J. Org. Chem., 1988, 54, 983-986; and N. Tsuji et al., J. Antibiot.,1988, 41, 819-822. The structure of this glycopeptide is similar tovancomycin, except A82846B contains an additional amino sugar (i.e.4-epi-vancosamine attached at the R² position in formula I.) and furthercontains 4-epi-vancosamine in place of vancosamine in the disaccharidemoiety attached at the R¹ position in formula I. For example, apreferred group of compounds are derivatives of A82846B that aresubstituted at the 4-epi-vancosamine nitrogen with a substituent thatcomprises one or more disulfide and thioester groups; or apharmaceutically acceptable salt, stereoisomer, or prodrug thereof.Another preferred group of compounds of the invention are derivatives ofA82846B wherein the 4-epi-vancosamine has been replaced with a groupselected from the values defined herein for R¹ in a compound of formulaI. The compounds of the invention that are disulfide and thioesterderivatives of A82846B can readily be prepared using the proceduresdescribed herein. Other preferred compounds of the invention arederivatives of A82846B wherein the 4-epi-vancosamine nitrogen issubstituted with a 4-(4-chlorophenyl)benzyl group or a4-(4-chlorobenzyloxy)benzyl group.

Representative compounds of the invention have been found tounexpectedly exhibit reduced tissue accumulation and/or nephrotoxicitywhen administered to a mammal. While not wishing to be bound by theory,it is believed that the disulfide or the thioester linkage functions asa metabolic sight that can be degraded in vivo, thereby facilitatingexcretion from the mammal after administration. The unexpected increasein excretion of the compounds of the invention may be responsible forthe reduced tissue accumulation and/or reduced nephrotoxicity observedfor these compounds relative to the corresponding compounds that lackthe disulfide or thioester functionality.

Additionally, it is possible that the thiol metabolites resulting fromthe metabolic degradation of the compounds of the invention can undergodimerization to form glycopeptide dimers that possess antibacterialactivity. Accordingly, the invention also provides dimers of the formulaG—R^(a)—B—R^(a)—G, wherein each G is independently a glycopeptide offormula I, bonded at the nitrogen of an R¹ saccharide; each R^(a)independently has one of the values defined herein for R^(a) in acompound of formula I; and B is —S—S—.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of the invention, which aredisulfide or thioester derivatives of glycopeptide antibiotics, as wellas to compositions comprising such compounds and to therapeutic methodscomprising the administration of such compounds. When describing thecompounds, compositions and methods of the invention, the followingterms have the following meanings, unless otherwise indicated.

Definitions

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 40 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to an alkyl group as defined above,having from 1 to 8 substituents, preferably 1 to 5 substituents, andmore preferably 1 to 3 substituents, selected from the group consistingof alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,guanido, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl,thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₃H, and —SO₂-heteroaryl.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 40 carbonatoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms.This term is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

The term “substituted alkylene” refers to an alkylene group, as definedabove, having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkylene groupsinclude those where 2 substituents on the alkylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkylene group. Preferably such fused groups contain from 1 to 3fused ring structures. Additionally, the term substituted alkyleneincludes alkylene groups in which from 1 to 5 of the alkylene carbonatoms are replaced with oxygen, sulfur or —NR— where R is hydrogen oralkyl. Examples of substituted alkylenes are chloromethylene (—CH(Cl)—),aminoethylene (—CH(NH₂)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—) and the like.

The term “alkaryl” refers to the groups -alkylene-aryl and -substitutedalkylene-aryl where alkylene, substituted alkylene and aryl are definedherein. Such alkaryl groups are exemplified by benzyl, phenethyl and thelike.

The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way ofexample, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy(—CH₂—O—C(CH₃)₃) and the like.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, byway of example, methylenethiomethoxy (—CH₂SCH₃), ethylenethiomethoxy(—CH₂CH₂SCH₃), n-propylene-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylene-t-thiobutoxy (—CH₂SC(CH₃)₃) and the like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH₂CH═CH— and—C(CH₃)═CH—) and the like.

The term “substituted alkenylene” refers to an alkenylene group asdefined above having from 1 to 5 substituents, and preferably from 1 to3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkenylene groupsinclude those where 2 substituents on the alkenylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkenylene group.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbonpreferably having from 2 to 40 carbon atoms, more preferably 2 to 20carbon atoms and even more preferably 2 to 6 carbon atoms and having atleast 1 and preferably from 1-6 sites of acetylene (triple bond)unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH) and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon preferably having from 2 to 40 carbon atoms, more preferably2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynylene groups include ethynylene(—C≡C—), propargylene (—CH₂C≡C—) and the like.

The term “substituted alkynylene” refers to an alkynylene group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl

The term “acyl” refers to the groups HC(O)—, alkyl—C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “acylamino” or “aminocarbonyl” refers to the group —C(O)NRRwhere each R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic or where both R groups are joined to form aheterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl,aryl, heteroaryl and heterocyclic are as defined herein.

The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

The term “aminoacyloxy” or “alkoxycarbonylamino” refers to the group—NRC(O)OR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings, wherein at least one ring is aromatic(e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferredaryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with from 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxy,carboxyalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, sulfonamide,thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

The term “arylene” refers to the diradical derived from aryl (includingsubstituted aryl) as defined above and is exemplified by 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic provided thatboth R's are not hydrogen.

“Amino acid” refers to any of the naturally occurring amino acids (e.g.Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys,Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D, L, or DL form. Theside chains of naturally occurring amino acids are well known in the artand include, for example, hydrogen (e.g., as in glycine), alkyl (e.g.,as in alanine, valine, leucine, isoleucine, proline), substituted alkyl(e.g., as in threonine, serine, methionine, cysteine, aspartic acid,asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl(e.g., as in phenylalanine and tryptophan), substituted arylalkyl (e.g.,as in tyrosine), and heteroarylalkyl (e.g., as in histidine).

The term “carboxy” refers to —COOH.

The term “C-terminus” as it relates to a glycopeptide is well understoodin the art. For example, for a glycopeptide of formula I, the C-terminusis the position substituted by the group R³.

The term “dicarboxy-substituted alkyl” refers to an alkyl groupsubstituted with two carboxy groups. This term includes, by way ofexample, —CH₂(COOH)CH₂COOH and —CH₂(COOH)CH₂CH₂COOH.

The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”,“—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substitutedalkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl alkynyl are asdefined herein.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “cycloalkylene” refers to a diradical of a cycloalkyl group.

The term “cycloalkyl” refers to cyclic alkenyl groups of from 4 to 20carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and thelike.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “cycloalkylene” refers to a diradical of a cycloalkyl group.

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to alkyl as defined herein substituted by 1-4 halogroups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfurwithin at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxy,carboxyalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl,pyrrolyl and furyl.

“Heteroarylalkyl” refers to (heteroaryl)alkyl- where heteroaryl andalkyl are as defined herein. Representative examples include2-pyridylmethyl and the like.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heteroarylene” refers to the diradical group derived fromheteroaryl (including substituted heteroaryl), as defined above, and isexemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl and the like.

The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated or unsaturated group having a single ring or multiplecondensed rings, from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1 to 3 substituents, selected from the groupconsisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, oxo (O═), and—SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Preferred heterocyclics include morpholino,piperidinyl, and the like.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

Another class of heterocyclics is known as “crown compounds” whichrefers to a specific class of heterocyclic compounds having one or morerepeating units of the formula [—(CH₂—)_(a)A—] where a is equal to orgreater than 2, and A at each separate occurrence can be O, N, S or P.Examples of crown compounds include, by way of example only,[—(CH₂)₃—NH—]₃, [—((CH₂)₂—O)₄—((CH₂)₂—NH)₂] and the like. Typically suchcrown compounds can have from 4 to 10 heteroatoms and 8 to 40 carbonatoms.

The term “heterocyclene refers to a diradical of a heterocycle group

The term “heterocyclooxy” refers to the group heterocyclic-O—.

The term “thioheterocyclooxy” refers to the group heterocyclic-S—.

The term “oxyacylamino” or “aminocarbonyloxy” refers to the group—OC(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “prodrug” is well understood in the art and includes compoundsthat are converted to pharmaceutically active compounds of the inventionin a mammalian system. For example, see Remington's PharmaceuticalSciences, 1980, vol. 16, Mack Publishing Company, Easton, Pa., 61 and424.

The term “saccharide group” refers to an oxidized, reduced orsubstituted saccharide monoradical covalently attached to theglycopeptide or other compound via any atom of the saccharide moiety,preferably via the aglycone carbon atom. The term includesamino-containing saccharide groups. Representative saccharides include,by way of illustration, hexoses such as D-glucose, D-mannose, D-xylose,D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, actinosamine, daunosamine,3-epi-daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine,D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine,sialyic acid, iduronic acid, L-fucose, and the like; pentoses such asD-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose;disaccharides such as 2-O-(α-L-vancosaminyl)-β-D-glucopyranose,2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose,or maltose; derivatives such as acetals, amines, acylated, sulfated andphosphorylated sugars; oligosaccharides having from 2 to 10 saccharideunits. For the purposes of this definition, these saccharides arereferenced using conventional three letter nomenclature and thesaccharides can be either in their open or preferably in their pyranoseform.

The term “amino-containing saccharide group” refers to a saccharidegroup having an amino substituent. Representative amino-containingsaccharides include L-vancosamine, 3-desmethyl-vancosamine,3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine,daunosamine, 3-epi-daunosamine, ristosamine, N-methyl-D-glucamine andthe like.

The term “spiro-attached cycloalkyl group” refers to a cycloalkyl groupattached to another ring via one carbon atom common to both rings.

The term “stereoisomer” as it relates to a given compound is wellunderstood in the art, and refers another compound having the samemolecular formula, wherein the atoms making up the other compound differin the way they are oriented in space, but wherein the atoms in theother compound are like the atoms in the given compound with respect towhich atoms are joined to which other atoms (e.g. an enantiomer, adiastereomer, or a geometric isomer). See for example, Morrison andBoyde Organic Chemistry, 1983, 4th ed., Allyn and Bacon, Inc., Boston,Mass., page 123

The term “sulfonamide” refers to a group of the formula —SO₂NRR, whereeach R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic are as defined herein.

The term “thiol” refers to the group —SH.

The term “thioalkoxy” refers to the group —S-alkyl.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined above including optionally substituted aryl groupsalso defined above.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined above including optionallysubstituted aryl groups as also defined above.

The term “thioether derivatives” when used to refer to the glycopeptidecompounds of this invention includes thioethers (—S—), sulfoxides (—SO—)and sulfones (—SO₂—).

As to any of the above groups which contain one or more substituents, itis understood, of course, that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisinvention include all stereochemical isomers arising from thesubstitution of these compounds.

“Cyclodextrin” refers to cyclic molecules containing six or moreα-D-glucopyranose units linked at the 1,4 positions by a linkages as inamylose. β-Cyclodextrin or cycloheptaamylose contains sevenα-D-glucopyranose units. As used herein, the term “cyclodextrin” alsoincludes cyclodextrin derivatives such as hydroxypropyl and sulfobutylether cyclodextrins. Such derivatives are described for example, in U.S.Pat. Nos. 4,727,064 and 5,376,645. One preferred cyclodextrin ishydroxypropyl β-cyclodextrin having a degree of substitution of fromabout 4.1-5.1 as measured by FTIR. Such a cyclodextrin is available fromCerestar (Hammond, Ind., USA) under the name Cavitron™ 82003.

“Glycopeptide” refers to oligopeptides (e.g. heptapeptide) antibiotics,characterized by a multi-ring peptide core optionally substituted withsaccharide groups, such as vancomycin. Examples of glycopeptidesincluded in this definition may be found in “GlycopeptidesClassification, Occurrence, and Discovery”, by Raymond C. Rao and LouiseW. Crandall, (“Drugs and the Pharmaceutical Sciences” Volume 63, editedby Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.). Additionalexamples of glycopeptides are disclosed in U.S. Pat. Nos. 4,639,433;4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889; inEP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO98/52589; WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118,13107-13108; J. Amer. Chem. Soc., 1997,119, 12041-12047; and J. Amer.Chem. Soc., 1994, 116, 4573-4590. Representative glycopeptides includethose identified as A477, A35512, A40926, A41030, A42867, A47934,A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin,Avoparcin, Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin,Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin, Helvecardin,Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761,MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653,Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin,UK-68597, UK-69542, UK-72051, Vancomycin, and the like. The term“glycopeptide” as used herein is also intended to include the generalclass of peptides disclosed above on which the sugar moiety is absent,i.e. the aglycone series of glycopeptides. For example, removal of thedisaccharide moiety appended to the phenol on vancomycin by mildhydrolysis gives vancomycin aglycone. Also within the scope of theinvention are glycopeptides that have been further appended withadditional saccharide residues, especially aminoglycosides, in a mannersimilar to vancosamine.

“Vancomycin” refers to a glycopeptide antibiotic having the formula:

When describing vancomycin derivatives, the term “N^(van)-” indicatesthat a substituent is covalently attached to the amino group of thevacosamine moiety of vacomycin. Similarly, the term “N^(leu)-” indicatesthat a substituent is covalently attached to the amino group of theleucine moiety of vancomycin.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted” means that a groupmay or may not be substituted with the described substitutent.

As used herein, the terms “inert organic solvent” or “inert solvent” or“inert diluent” mean a solvent or diluent which is essentially inertunder the conditions of the reaction in which it is employed as asolvent or diluent. Representative examples of materials which may beused as inert solvents or diluents include, by way of illustration,benzene, toluene, acetonitrile, tetrahydrofuran (“THF”),dimethylformamide (“DMF”), chloroform (“CHCl₃”), methylene chloride (ordichloromethane or “CH₂Cl₂), diethyl ether, ethyl acetate, acetone,methylethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

The term “nitrogen-linked” means a group or substituent is attached tothe remainder of a compound (e.g. a compound of formula I) through abond to a nitrogen of the group or substituent.

“Pharmaceutically acceptable salt” means those salts which retain thebiological effectiveness and properties of the parent compounds andwhich are not biologically or otherwise harmful as the dosageadministered. The compounds of this invention are capable of formingboth acid and base salts by virtue of the presence of amino and carboxygroups respectively.

Pharmaceutically acceptable base addition salts may be prepared frominorganic and organic bases. Salts derived from inorganic bases include,but are not limited to, the sodium, potassium, lithium, ammonium,calcium, and magnesium salts. Salts derived from organic bases include,but are not limited to, salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines, including isopropylamine, trimethyl amine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine, andN-ethylpiperidine. It should also be understood that other carboxylicacid derivatives would be useful in the practice of this invention, forexample carboxylic acid amides, including carboxamides, lower alkylcarboxamides, di(lower alkyl) carboxamides, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

The compounds of this invention typically contain one or more chiralcenters. Accordingly, this invention is intended to include racemicmixtures, diasteromers, enantiomers and mixture enriched in one or moresteroisomer. The scope of the invention as described and claimedencompasses the racemic forms of the compounds as well as the individualenantiomers and non-racemic mixtures thereof.

The term “treatment” as used herein includes any treatment of acondition or disease in an animal, particularly a mammal, moreparticularly a human, and includes:

-   -   (i) preventing the disease or condition from occurring in a        subject which may be predisposed to the disease but has not yet        been diagnosed as having it;    -   (ii) inhibiting the disease or condition, i.e. arresting its        development; relieving the disease or condition, i.e. causing        regression of the condition; or relieving the conditions caused        by the disease, i.e. symptoms of the disease.

The term “disease state which is alleviated by treatment with a broadspectrum antibacterial” or “bacterial disease” as used herein isintended to cover all disease states which are generally acknowledged inthe art to be usefully treated with a broad spectrum antibacterial ingeneral, and those disease states which have been found to be usefullytreated by the specific antibacterials of this invention. Such diseasestates include, but are not limited to, treatment of a mammal afflictedwith pathogenic bacteria, in particular staphylococci (methicillinsensitive and resistant), streptococci (penicillin sensitive andresistant), enterococci (vancomycin sensitive and resistant), andClostridium difficile

The term “therapeutically effective amount” refers to that amount whichis sufficient to effect treatment, as defined herein, when administeredto a mammal in need of such treatment. The therapeutically effectiveamount will vary depending on the subject and disease state beingtreated, the severity of the affliction and the manner ofadministration, and may be determined routinely by one of ordinary skillin the art.

The term “protecting group” or “blocking group” refers to any groupwhich, when bound to one or more hydroxyl, thiol, amino, carboxy orother groups of the compounds, prevents undesired reactions fromoccurring at these groups and which protecting group can be removed byconventional chemical or enzymatic steps to reestablish the hydroxyl,thio, amino, carboxy or other group. The particular removable blockinggroup employed is not critical and preferred removable hydroxyl blockinggroups include conventional substituents such as allyl, benzyl, acetyl,chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyland any other group that can be introduced chemically onto a hydroxylfunctionality and later selectively removed either by chemical orenzymatic methods in mild conditions compatible with the nature of theproduct. Protecting groups are disclosed in more detail in T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis” 3^(rd) Ed.,1999, John Wiley and Sons, N.Y.

Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC) and the like,which can be removed by conventional conditions compatible with thenature of the product.

Preferred carboxy protecting groups include esters such as methyl,ethyl, propyl, t-butyl etc. which can be removed by mild conditionscompatible with the nature of the product.

General Synthetic Procedures

The glycopeptide compounds of this invention can be prepared fromreadily available starting materials using the following general methodsand procedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

In the following reaction schemes, the glycopeptide compounds aredepicted in a simplified form as a box “G” that shows the carboxyterminus labeled [C], the vancosamine amino terminus labeled [V], the“non-saccharide” amino terminus (leucine amine moiety) labeled [N], andoptionally, the resorcinol moiety labeled [R] as follows:

By way of illustration, a glycopeptide compound, such as vancomycin, canbe reductive alkylated as shown in the following reaction:

where A represents R^(a) minus one carbon atom and R^(a), R^(h), and Ware as defined herein. This reaction is typically conducted by firstcontacting one equivalent of the glycopeptide, e.g., vancomycin, with anexcess, preferably from 1.1 to 1.3 equivalents, of the aldehyde in thepresence of an excess, preferably about 2.0 equivalents, of a tertiaryamine, such as diisopropylethylamine (DIPEA) and the like. This reactionis typically conducted in an inert diluent, such as DMF oracetonitrile/water, at ambient temperature for about 0.25 to 2 hoursuntil formation of the corresponding imine and/or hemiaminal issubstantially complete. The resulting imine and/or hemiaminal istypically not isolated, but is reacted in situ with a metal hydridereducing agent, such as sodium cyanoborohydride or the like, to affordthe corresponding amine. This reaction is preferably conducted bycontacting the imine and/or hemiaminal with an excess, preferably about3 equivalents, of trifluoroacetic acid, followed by about 1 to 1.2equivalents of the reducing agent at ambient temperature in methanol oracetonitrile/water. The resulting alkylated product is readily purifiedby conventional procedures, such as precipitation and/or reverse-phaseHPLC. Surprisingly, by forming the imine and/or hemiaminal in thepresence of a trialkyl amine, and then acidifying with trifluoroaceticacid before contact with the reducing agent, the selectivity for thereductive alkylation reaction is greatly improved, i.e., reductivealkylation at the amino group of the saccharide (e.g., vancosamine) isfavored over reductive alkylation at the N-terminus (e.g., the leucinylgroup) by at least 10:1, more preferably 20:1.

The above process is a significant improvement over previous methods forselectively alkylating an amino saccharide group of a glycopeptideantibiotic. Thus, the present invention also provides a method foralkylating a glycopeptide that comprises a saccharide-amine comprising:

-   -   combining an aldehyde or ketone, a suitable base, and the        glycopeptide, to provide a reaction mixture;    -   acidifying the reaction mixture; and    -   combining the reaction mixture with a suitable reducing agent,        to provide a glycopeptide that is alkylated at the        saccharide-amine. Preferably, the glycopeptide comprises at        least one amino group other than the saccharide-amine.

Preferably, the reductive alkylation at the saccharide-amine is favoredover reductive alkylation at another amino group of the glycopeptide byat least about 10:1; and more preferably, by at least about 15:1 orabout 20:1.

The reductive alkylation process of the invention is typically carriedout in the presence of a suitable solvent or combination of solvents,such as, for example, a halogenated hydrocarbon (e.g. methylenechloride), a linear or branched ether (e.g. diethyl ether,tetrahydrofuran), an aromatic hydrocarbon (e.g. benzene or toluene), analcohol (methanol, ethanol, or isopropanol), dimethylsulfoxide (DMSO),N,N-dimethylformamide, acetonitrile, water,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, tetramethyl urea,N,N-dimethylacetamide, diethylformamide (DMF), 1-methyl-2-pyrrolidinone,tetramethylenesulfoxide, glycerol, ethyl acetate, isopropyl acetate,N,N-dimethylpropylene urea (DMPU) or dioxane. Preferably the alkylationis carried out in acetonitrile/water, or DMF/methanol.

Preferably the reduction (i.e. treatment with the reducing agent) iscarried out in the presence of a protic solvent, such as, for example,an alcohol (e.g. methanol, ethanol, propanol, isopropanol, or butanol),water, or the like.

The reductive alkylation process of the invention can be carried out atany suitable temperature from the freezing point to the refluxtemperature of the reaction mixture. Preferably the reaction is carriedout at a temperature in the range of about 0° C. to about 100° C. Morepreferably at a temperature in a range of about 0° C. to about 50° C.,or in a range of about 20° C. to about 30° C.

Any suitable base can be employed in the reductive alkylation process ofthe invention. Suitable bases include tertiary amines (e.g.diisopropylethylamine, N-methylmorpholine or triethylamine) and thelike.

Any suitable acid can be used to acidify the reaction mixture. Suitableacids include carboxylic acids (e.g. acetic acid, trichloroacetic acid,citric acid, formic acid, or trifluoroacetic acid), mineral acids (e.g.hydrochloric acid, sulfuric acid, or phosphoric acid), and the like. Apreferred acid is trifluoroacetic acid.

Suitable reducing agents for carrying out reductive alkylation processof the invention are known in the art. Any suitable reducing agent canbe employed in the methods of the invention, provided it is compatiblewith the functionality present in the glycopeptide. For example,suitable reducing agents include sodium cyanoborohydride,triacetoxyborohydride, pyridine/borane, sodium borohydride, and zincborohydride. The reduction can also be carried out in the presence of atransition metal catalyst (e.g. palladium or platinum) in the presenceof a hydrogen source (e.g. hydrogen gas or cycloheadiene). See forexample, March, Advanced Organic Chemistry, Fourth Edition, John Wiley &Sons, New York (1992), 899-900.

If desired, the glycopeptide compounds of the invention can also beprepared in a step-wise manner in which a precursor to the—R^(g)—W—R^(h) group is first attached the glycopeptide by reductivealkylation, followed by subsequent elaboration of the attached precursorusing conventional reagent and procedures to form the —R^(g)—W—R^(h)group. Additionally, ketones may also be employed in the above-describedreductive alkylation reactions to afford α-substituted amines.

Any glycopeptide having an amino group may be employed in thesereductive alkylation reactions. Such glycopeptides are well-known in theart and are either commercially available or may be isolated usingconventional procedures. Suitable glycopeptides are disclosed, by way ofexample, in U.S. Pat. Nos. 3,067,099; 3,338,786; 3,803,306; 3,928,571;3,952,095; 4,029,769; 4,051,237; 4,064,233; 4,122,168; 4,239,751;4,303,646; 4,322,343; 4,378,348; 4,497,802; 4,504,467; 4,542,018;4,547,488; 4,548,925; 4,548,974; 4,552,701; 4,558,008; 4,639,433;4,643,987; 4,661,470; 4,694,069; 4,698,327; 4,782,042; 4,914,187;4,935,238; 4,946,941; 4,994,555; 4,996,148; 5,187,082; 5,192,742;5,312,738; 5,451,570; 5,591,714; 5,721,208; 5,750,509; 5,840,684; and5,843,889. Preferably, the glycopeptide employed in the above reactionis vancomycin.

As illustrated in the following scheme, an aminoalkyl sidechain at theresorcinol moiety of a glycopeptide, such as vancomycin, can beintroduced via a Mannich reaction (in this scheme, the resorcinol moietyis shown for clarity). In this reaction, an amine (NHR^(c)R^(c)) and analdehyde (CH₂O), such as formalin (a source of formaldehyde), arereacted with the glycopeptide under basic conditions to give theglycopeptide derivative.

Compounds of the invention comprising a sulfoxide or sulfone can beprepared from the corresponding thio compounds using conventionalreagents and procedures. Suitable reagents for oxidizing a thio compoundto a sulfoxide include, by way of example, hydrogen peroxide, peracidessuch as 3-chloroperoxybenzoic acid (MCPBA), sodium periodate, sodiumchlorite, sodium hypochlorite, calcium hypochlorite, tert-butylhypochlorite and the like. Chiral oxidizing reagents, (optically activereagents) may also be employed to provide chiral sulfoxides. Suchoptically active reagents are well-known in the art and include, forexample, the reagents described in Kagen et al., Synlett., 1990,643-650.

The aldehydes and ketones employed in the above reactive alkylationreactions are also well-known in the art and are either commerciallyavailable or can be prepared by conventional procedures usingcommercially available starting materials and conventional reagents (forexample see March, Advanced Organic Chemistry, Fourth Edition, JohnWiley & Sons, New York (1992), and references cited therein).

For example, aldehydes comprising a disulfide group are eithercommercially available or can be prepared by conventional proceduresusing commercially available starting materials and reagents.Additionally, aldehydes comprising a disulfide group can be prepared asillustrated in Scheme I.

Activation of compound 1 with diethyl azodicarboxylate (DEAD) andtreatment with thiol (RSH) provides disulfide 2, which can be reduced,for example with diisobutylaluminum hydride (DIBAH-H) to providealdehyde 3. Alternatively, intermediate compound 2 can be prepared fromcompound 1 by iodine oxidation in the presence of RSH.

Aldehydes comprising a thioester group are either commercially availableor can be prepared by conventional procedures using commerciallyavailable starting materials and reagents. Additionally, aldehydescomprising a thioester group can be prepared as illustrated in thefollowing Scheme 2.

Treatment of bromide 4 with thiourea provides thiol 5, which can beesterified by treatment with RCOCl to provide thioester 6. Subsequentacid catalyzed hydrolysis of the acetal provides aldehyde 9.Alternatively, ester 7 can be treated with RCOCl to provide a compoundof formula 8, which can subsequently be reduced, for example usingDIBAL-H, to provide the aldehyde 9.

Additional details and other methods for preparing the compounds of theinvention are described in the Examples below.

Pharmaceutical Compositions

This invention also includes pharmaceutical composition containing thenovel glycopeptide compounds of this invention. Accordingly, theglycopeptide compound, preferably in the form of a pharmaceuticallyacceptable salt, can be formulated for oral or parenteral administrationfor the therapeutic or prophylactic treatment of bacterial infections.

By way of illustration, the glycopeptide compound can be admixed withconventional pharmaceutical carriers and excipients and used in the formof tablets, capsules, elixirs, suspensions, syrups, wafers, and thelike. Such pharmaceutical compositions will contain from about 0.1 toabout 90% by weight of the active compound, and more generally fromabout 10 to about 30%. The pharmaceutical compositions may containcommon carriers and excipients, such as corn starch or gelatin, lactose,sucrose, microcrystalline cellulose, kaolin, mannitol, dicalciumphosphate, sodium chloride, and alginic acid. Disintegrators commonlyused in the formulations of this invention include croscarmellose,microcrystalline cellulose, corn starch, sodium starch glycolate andalginic acid.

A liquid composition will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, optionally with asuspending agent, a solubilizing agent (such as a cyclodextrin),preservative, surfactant, wetting agent, flavoring or coloring agent.Alternatively, a liquid formulation can be prepared from areconstitutable powder.

For example a powder containing active compound, suspending agent,sucrose and a sweetener can be reconstituted with water to form asuspension; and a syrup can be prepared from a powder containing activeingredient, sucrose and a sweetener.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch and ethylcellulose. Lubricants that canbe used include magnesium stearate or other metallic stearates, stearicacid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

The compounds of the invention and their pharmaceutically acceptablesalts that are active when given parenterally can be formulated forintramuscular, intrathecal, or intravenous administration.

A typical composition for intramuscular or intrathecal administrationwill consist of a suspension or solution of active ingredient in an oil,for example arachis oil or sesame oil. A typical composition forintravenous or intrathecal administration will consist of a sterileisotonic aqueous solution containing, for example active ingredient anddextrose or sodium chloride, or a mixture of dextrose and sodiumchloride. Other examples are lactated Ringer's injection, lactatedRinger's plus dextrose injection, Normosol-M and dextrose, Isolyte E,acylated Ringer's injection, and the like. Optionally, a co-solvent, forexample, polyethylene glycol; a chelating agent, for example,ethylenediamine tetracetic acid; a solubilizing agent, for example, acyclodextrin; and an anti-oxidant, for example, sodium metabisulphite,may be included in the formulation. Alternatively, the solution can befreeze dried and then reconstituted with a suitable solvent just priorto administration.

In a preferred embodiment, the glycopeptide derivatives of thisinvention are formulated in an aqueous solution containing acyclodextrin. In another preferred embodiment the glycopeptidederivatives of this invention are formulated as a lyophilized powdercontaining a cyclodextrin or as a sterile powder containing acyclodextrin. Preferably, the cyclodextrin ishydroxypropyl-β-cyclodextrin or sulfobutyl ether β-cyclodextrin; morepreferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Typically,in an injectable solution, the cyclodextrin will comprise about 1 to 25weight percent; preferably, about 2 to 10 weight percent; morepreferable, about 4 to 6 weight percent, of the formulation.Additionally, the weight ratio of the cyclodextrin to the glycopeptidederivative will preferably be from about 1:1 to about 10:1.

The compounds of the invention and their pharmaceutically acceptablesalts which are active on rectal administration can be formulated assuppositories. A typical suppository formulation will generally consistof active ingredient with a binding and/or lubricating agent such as agelatin or cocoa butter or other low melting vegetable or synthetic waxor fat.

The compounds of this invention and their pharmaceutically acceptablesalts which are active on topical administration can be formulated astransdermal compositions or transdermal delivery devices (“patches”).Such compositions include, for example, a backing, active compoundreservoir, a control membrane, liner and contact adhesive. Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Suitable doses are in the general range of from 0.01-100 mg/kg/day,preferably 0.1-50 mg/kg/day. For an average 70 kg human, this wouldamount to 0.7 mg to 7 g per day, or preferably 7 mg to 3.5 g per day. Amore preferred dose for a human is about 500 mg to about 2 g per day.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

The following formulation examples illustrate representativepharmaceutical compositions of the present invention.

FORMULATION EXAMPLE A

This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention:

Ingredients Quantity per tablet, (mg) Active Compound 200 Lactose,spray-dried 148 Magnesium stearate  2The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

FORMULATION EXAMPLE B

This example illustrates the preparation of another representativepharmaceutical composition for oral administration of a compound of thisinvention:

Ingredients Quantity per tablet, (mg) Active Compound 400 Cornstarch  50Lactose 145 Magnesium stearate  5The above ingredients are mixed intimately and pressed into singlescored tablets.

FORMULATION EXAMPLE C

This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention.

An oral suspension is prepared having the following composition.

Ingredients Active Compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0g Methyl paraben 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 mL

FORMULATION EXAMPLE D

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

An injectable preparation buffered to a pH of 4 is prepared having thefollowing composition:

Ingredients Active Compound 0.2 g Sodium Acetate Buffer Solution (0.4 M)2.0 mL HCl (1 N) q.s. to pH 4 Water (distilled, sterile) q.s. to  20 mL

FORMULATION EXAMPLE E

This example illustrates the preparation of a representativepharmaceutical composition for injection of a compound of thisinvention.

A reconstituted solution is prepared by adding 20 mL of sterile water to1 g of the compound of this invention. Before use, the solution is thendiluted with 200 mL of an intravenous fluid that is compatible with theactive compound. Such fluids are chosen from 5% dextrose solution, 0.9%sodium chloride, or a mixture of 5% dextrose and 0.9% sodium chloride.Other examples are lactated Ringer's injection, lactated Ringer's plus5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, andacylated Ringer's injection

FORMULATION EXAMPLE F

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

An injectable preparation is prepared having the following composition:

Ingredients Active Compound 0.1-5.0 g Hydroxypropyl-β-cyclodextrin 1-25g 5% Aqueous Dextrose Solution (sterile) q.s. to 100 mLThe above ingredients are blended and the pH is adjusted to 3.5±0.5using 0.5 N HCl or 0.5 N NaOH.

FORMULATION EXAMPLE G

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

A frozen solution suitable for injection is prepared having thefollowing composition:

Frozen Solution Active Compound 250 mg to 1000 mgHydroxypropyl-β-cyclodextrin 250 mg to 10 g Excipients - e.g., dextrose0-50 g Water for Injection 10-100 mL

The weight ratio of hydroxypropyl-β-cyclodextrin to the active compoundwill typically be from about 1:1 to about 10:1.

Representative Procedure: Hydroxypropyl-β-cyclodextrin and excipients,if any, are dissolved in about 80% of the water for injection and theactive compound is added and dissolved. The pH is adjusted with 1 Msodium hydroxide to 4.7±0.3 and the volume is then adjusted to 95% ofthe final volume with water for injection. The pH is checked andadjusted, if necessary, and the volume is adjusted to the final volumewith water for injection. The formulation is then sterile filteredthrough a 0.22 micron filter and placed into a sterile vial underaseptic conditions. The vial is capped, labeled and stored frozen.

FORMULATION EXAMPLE H

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

A lyophilized powder useful for preparing an injectable solution isprepared having the following composition:

Lyophilized Powder Active Compound 250 mg to 1000 mgHydroxypropyl-β-cyclodextrin 250 mg to 10 g Excipients - e.g., mannitol,0-50 g sucrose and/or lactose Buffer agent - e.g., citrate 0-500 mg

The weight ratio of hydroxypropyl-β-cyclodextrin to the active compoundwill typically be from about 1:1 to about 10:1.

Representative Procedure: Hydroxypropyl-β-cyclodextrin and excipientsand/or buffering agents, if any, are dissolved in about 60% of the waterfor injection. The active compound is added and dissolved and the pH isadjusted with 1 M sodium hydroxide to 4.0-5.0 and the volume is adjustedto 95% of the final volume with water for injection. The pH is checkedand adjusted, if necessary, and the volume is adjusted to the finalvolume with water for injection. The formulation is then sterilefiltered through a 0.22 micron filter and placed into a sterile vialunder aseptic conditions. The formulation is then freeze-dried using anappropriate lyophilization cycle. The vial is capped (optionally underpartial vacuum or dry nitrogen), labeled and stored at room temperatureor under refrigeration.

FORMULATION EXAMPLE I

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

A sterile powder useful for preparing an injectable solution is preparedhaving the following composition:

Sterile Powder Active Compound 250 mg to 1000 mgHydroxypropyl-β-cyclodextrin 250 mg to 10 g¹ Excipients To be determined

The weight ratio of hydroxypropyl-β-cyclodextrin to the active willtypically be from about 1:1 to about 10:1.

Representative Procedure: Hydroxypropyl-β-cyclodextrin and the activecompound (and any excipients) are dispersed into an appropriate sterilecontainer and the container is sealed (optionally under partial vacuumor dry nitrogen), labeled and stored at room temperature or underrefrigeration.

Administration of Representative Formulations H and I to a Patient

The pharmaceutical formulations described in formulation examples H andI above can be administered intravenously to a patient by theappropriate medical personnel to treat or prevent gram-positiveinfections. For administration, the above formulations can bereconstituted and/or diluted with a diluent, such as 5% dextrose orsterile saline, as follows:

Representative Procedure: The lyophilized powder of formulation exampleH (e.g., containing 1000 mg of active compound) is reconstituted with 20mL of sterile water and the resulting solution is further diluted with80 mL of sterile saline in a 100 mL infusion bag. The diluted solutionis then administered to the patient intravenously over 30 to 120minutes.

FORMULATION EXAMPLE J

This example illustrates the preparation of a representativepharmaceutical composition for topical application of a compound of thisinvention.

Ingredients grams Active compound  0.2-10 Span 60  2 Tween 60  2 Mineraloil  5 Petrolatum  10 Methyl paraben  0.15 Propyl paraben  0.05 BHA(butylated hydroxy anisole)  0.01 Water q.s. to 100All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

FORMULATION EXAMPLE K

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

A suppository totaling 2.5 grams is prepared having the followingcomposition:

Ingredients Active Compound 500 mg Witepsol H-15* balance *triglyceridesof saturated vegetable fatty acid; a product of Riches-Nelson, Inc., NewYork, N.Y.Utility

The glycopeptide compounds of this invention, and their pharmaceuticallyacceptable salts, are useful in medical treatments and exhibitbiological activity, including antibacterial activity, which can bedemonstrated in using the tests described herein. Such tests are wellknown to those skilled in the art, and are referenced and described inLorian “Antibiotics in Laboratory Medicine”, Fourth Edition, Williamsand Wilkins (1991).

Accordingly, this invention provides methods for treating bacterial orinfectious diseases, especially those caused by Gram-positivemicroorganisms, in animals. The compounds of this invention areparticularly useful in treating infections caused bymethicillin-resistant staphylococci. Also, the compounds are useful intreating infection due to enterococci, including vancomycin-resistantenterococci (VRE). Examples of such diseases include severestaphylococcal infections, such as staphylococcal endocarditis andstaphylococcal septicemia. The animal treated may be either susceptibleto, or infected with, the microorganism. The method of treatmenttypically comprises administering to the animal an amount of a compoundof this invention which is effective for this purpose.

In practicing this method, the antibiotic can be administered in asingle daily dose or in multiple doses per day. The treatment regimenmay require administration over extended periods of time, for example,for several days or for from one to six weeks. The amount peradministered dose or the total amount administered will depend on suchfactors as the nature and severity of the infection, the age and generalhealth of the patient, the tolerance of the patient to the antibioticand the microorganism or microorganisms in the infection.

Among other properties, the glycopeptide compounds of the invention havebeen found to have reduced mammalian toxicity when administered to amammal. For example, the disulfide or thioester derivatives of theinvention have been found to have reduced liver and/or kidneyaccumulation compared to the corresponding compounds that lack thedisulfide or thioester group(s). Moreover, certain compounds of theinvention are expected to have reduced nephrotoxicity. Additionally, ithas been discovered that the addition of a cyclodextrin compound to apharmaceutical composition containing the glycopeptide compounds of thisinvention further reduces the nephrotoxicity and/or tissue accumulationof the glycopeptide compound when administered to a mammal.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. Any abbreviations not defined have their generally acceptedmeaning. Unless otherwise stated, all temperatures are in degreesCelsius.

-   -   ACN=acetonitrile    -   BOC, Boc=tert-butoxycarbonyl    -   DIBAL-H=diisobutylaluminum hydride    -   DIPEA=diisopropylethylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   eq.=equivalent    -   EtOAc=ethyl acetate    -   Fmoc=9-fluorenylmethoxycarbonyl    -   HOBT=1-hydroxybenzotriazole hydrate    -   Me=methyl    -   PyBOP=benzotriazol-1-yloxytris(pyrrolidino)phosphonium        hexafluorophosphate    -   TEMPO=2,2,6,6-tetramethyl-piperidinyloxy, free radical    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC, tlc=thin layer chromatography

In the following examples, vancomycin hydrochloride semi-hydrate waspurchased from Alpharma, Inc. Fort Lee, N.J. 07024 (Alpharma AS, OsloNorway). Other reagents and reactants are available from AldrichChemical Co., Milwaukee, Wis. 53201.

General Procedure A Reductive Alkylation of Vancomycin

To a mixture of vancomycin (1 eq.) and the desired aldehyde (1.3 eq.) inDMF was added DIPEA (2 eq.). The reaction was stirred at ambienttemperature for 1-2 hours and monitored by reverse-phase HPLC. Methanoland NaCNBH₃ (1 eq.) were added to the solution, followed by TFA (3 eq.).Stirring was continued for an additional hour at ambient temperature.After the reaction was complete, the methanol was removed in vacuo. Theresidue was precipitated in acetonitrile. Filtration gave the crudeproduct which was then purified by reverse-phase HPLC. If desired, otherglycopeptides antibiotics may be used in this procedure.

General Procedure B Preparation of MeOC(O)CH₂SSC₈H₁₇

In a N₂ purged flask there was dissolved Diethyl azodicarboxylate (5.0g, 28.71 mmol) in dichloromethane (150 mL). A solution of Methylthioglycolate (2.89 g, 27.27 mmol) in dichloromethane (50 mL) was thenadded dropwise at room temperature over 20 minutes. After 1.5 hoursstirring, a solution of octanethiol (4.8 mL, 27.27 mmol) indichloromethane (50 mL) was added dropwise over 20 minutes, and theresulting solution was stirred for an additional 12 hours at roomtemperature. The solvent was then removed under reduced pressure, andthe resulting oil was then purified over flash silica with 5% ethylacetate in hexanes to yield MeOC(O)CH₂SSC₈H₁₇ as a clear, colorless oil.

General Procedure C Preparation of OHCCH₂SSC₈H₁₇

MeOC(O)CH₂SSC₈H₁₇ (1.85 g, 7.39 mmol) was dissolved in dry diethyl ether(40 mL) in a N₂ purged flask. The solution was cooled to −78° C., andDIBAL-H (8.87 mL, 1.0 M in cyclohexane, 8.87 mmol) was added to the coldsolution dropwise via syringe. The reaction was stirred at −78° C. for 1h 45 min, after which H₂O (5 mL) was added, the cold bath removed andthe solution was allowed to slowly warm to room temperature. Additionaldiethyl ether (60 mL) was added, and the organic phase was washed with1N HCl (3×100 mL), dried over MgSO₄, and concentrated to yieldHC(O)CH₂SSC₈H₁₇ (1.58 g, 97.02%) as a milky oil.

Example 1 Preparation of Compound 1

Using general reductive alkylation procedure A described above, and thefollowing amounts of materials, the title compound was prepared.

Amounts:

-   -   HC(O)CH₂SSC₈H₁₇ (1.58 g, 7.17 mmol)    -   Vancomycin (10.65 g, 7.17 mmol)    -   Diisopropylethyl amine (2.5 mL, 14.20 mmol)    -   TFA (1.66 mL, 21.51 mmol)    -   NaCNBH₃ (1.35 g, 21.51 mmol)        Once reduction of the imine was complete as evidenced by HPLC,        the reaction mixture was poured into diethyl ether, and the        resulting ppt was filtered. The crude product was purified by        reverse phase HPLC to yield the title compound. MS calculated        (M+) 1653.7; found (MH+)1654.4.

Using the above procedures and the appropriate starting materials thecompounds shown in Table I were prepared. The mass spectral data forthese compounds were as follows:

Compound No. MW (freebase) Observed MH⁺ 1 1653.7 1654.4 2 1667.71 1668.83 1667.71 1668.5 4 1681.74 1682.8

Example 2 Determination of Antibacterial Activity

A. In Vitro Determination of Antibacterial Activity

1. Determination of Minimal Inhibitory Concentrations (MICs)

Bacterial strains were obtained from either American Type Tissue CultureCollection (ATCC), Stanford University Hospital (SU), Kaiser PermanenteRegional Laboratory in Berkeley (KPB), Massachusetts General Hospital(MGH), the Centers for Disease Control (CDC), the San FranciscoVeterans' Administration Hospital (SFVA) or the University of CaliforniaSan Francisco Hospital (UCSF). Vancomycin resistant enterococci werephenotyped as Van A or Van B based on their sensitivity to teicoplanin.Some vancomycin resistant enterococci that had been genotyped as Van A,Van B, Van C1 or Van C2 were obtained from the Mayo Clinic.

Minimal inhibitory concentrations (MICs) were measured in amicrodilution broth procedure under NCCLS guidelines. Routinely, thecompounds were serially diluted into Mueller-Hinton broth in 96-wellmicrotiter plates. Overnight cultures of bacterial strains were dilutedbased on absorbance at 600 nm so that the final concentration in eachwell was 5×10 cfu/mL. Plates were returned to a 35° C. incubator. Thefollowing day (or 24 hours in the case of Enterococci strains), MICswere determined by visual inspection of the plates. Strains routinelytested in the initial screen included methicillin-sensitiveStaphylococcus aureus (MSSA), methicillin-resistant Staphylococcusaureus, methicillin-sensitive Staphylococcus epidermidis (MSSE),methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycinsensitive Enterococcus faecium (VSE Fm), vancomycin sensitiveEnterococcus faecalis (VSE Fs), vancomycin resistant Enterococcusfaecium also resistant to teicoplanin (VRE Fm Van A), vancomycinresistant Enterococcus faecium sensitive to teicoplanin (VRE Fm Van B),vancomycin resistant Enterococcus faecalis also resistant to teicoplanin(VRE Fs Van A), vancomycin resistant Enterococcus faecalis sensitive toteicoplanin (VRE Fs Van B), enterococcus gallinarium of the Van Agenotype (VRE Gm Van A), enterococcus gallinarium of the Van C-1genotype (VRE Gm Van C-1), enterococcus casseliflavus of the Van C-2genotype (VRE Cs Van C-2), enterococcus flavescens of the Van C-2genotype (VRE Fv Van C-2), and penicillin-sensitive Streptococcuspneumoniae (PSSP) and penicillin-resistant Streptococcus pneumoniae(PSRP). Because of the inability of PSSP and PSRP to grow well inMueller-Hinton broth, MICs with those strains were determined usingeither TSA broth supplemented with defibrinated blood or blood agarplates. Compounds which had significant activity against the strainsmentioned above were then tested for MIC values in a larger panel ofclinical isolates including the species listed above as well asnon-speciated coagulase negative Staphylococcus both sensitive andresistant to methicillin (MS-CNS and MR-CNS). In addition, they weretested for MICs against gram negative organisms, such as Escherichiacoli and Pseudomonas aeruginosa.

2. Determination of Kill Time

Experiments to determine the time required to kill the bacteria wereconducted as described in Lorian, “Antibiotics in Laboratory Medicine”,Fourth Edition, Williams and Wilkins (1991). These experiments wereconducted normally with both staphylococcus and enterococcus strains.

Briefly, several colonies were selected from an agar plate and grown at35° C. under constant agitation until it achieved a turbidity ofapproximately 1.5 and 10⁸ CFU/mL. The sample was then diluted to about6×10⁶ CFU/mL and incubated at 35° C. under constant agitation wascontinued. At various times aliquots were removed and five ten-foldserial dilutions were performed. The pour plate method was used todetermine the number of colony forming units (CFUs).

In general, the compounds of the invention were active in the abovetests in vitro tests and demonstrated a broad spectrum of activity.

B. In Vivo Determination of Antibacterial Activity

1. Acute Tolerability Studies in Mice

In these studies, a compound of this invention was administered eitherintravenously or subcutaneously and observed for 5-15 minutes. If therewere no adverse effects, the dose was increased in a second group ofmice. This dose incrementation continued until mortality occurred, orthe dose was maximized. Generally, dosing began at 20 mg/kg andincreased by 20 mg/kg each time until the maximum tolerated dose (MTD)is achieved.

2. Bioavailability Studies in Mice

Mice were administered a compound of this invention either intravenouslyor subcutaneously at a therapeutic dose (in general, approximately 50mg/kg). Groups of animals were placed in metabolic cages so that urineand feces could be collected for analysis. Groups of animals (n=3) weresacrificed at various times (10 min, 1 hour and 4 hours). Blood wascollected by cardiac puncture and the following organs wereharvested—lung, liver, heart, brain, kidney, and spleen. Tissues wereweighed and prepared for HPLC analysis. HPLC analysis on the tissuehomogenates and fluids was used to determine the concentration of thetest compound or IiI present. Metabolic products resulting from changesto the test compound were also determined at this juncture.

3. Mouse Septicemia Model

In this model, an appropriately virulent strain of bacteria (mostcommonly S. aureus, or E. Faecalis or E. Faecium) was administered tomice (N=5 to 10 mice per group) intraperitoneally. The bacteria wascombined with hog gastric mucin to enhance virulence. The dose ofbacteria (normally 10⁵-10⁷) was that sufficient to induce mortality inall of the mice over a three day period. One hour after the bacteria wasadministered, a compound of this invention was administered in a singledose either IV or subcutaneously. Each dose was administered to groupsof 5 to 10 mice, at doses that typically ranged from a maximum of about20 mg/kg to a minimum of less than 1 mg/kg. A positive control (normallyvancomycin with vancomycin sensitive strains) was administered in eachexperiment. The dose at which approximately 50% of the animals are savedwas calculated from the results.

4. Neutropenic Thigh Model

In this model, antibacterial activity of a compound of this inventionwas evaluated against an appropriately virulent strain of bacteria (mostcommonly S. aureus, or E. Faecalis or E. Faecium, sensitive or resistantto vancomycin). Mice were initially rendered neutropenic byadministration of cyclophosphamide at 200 mg/kg on day 0 and day 2. Onday 4 they were infected in the left anterior thigh by an IM injectionof a single dose of bacteria. The mice were then administered the testcompound one hour after the bacteria and at various later times(normally 1, 2.5, 4 and 24 hours) the mice were sacrificed (3 per timepoint) and the thigh excised, homogenized and the number of CFUs (colonyforming units) were determined by plating. Blood was also plated todetermine the CFUs in the blood.

5. Pharmacokinetic Studies

The rate at which a compound of this invention is removed from the bloodcan be determined in either rats or mice. In rats, the test animals werecannulated in the jugular vein. The test compound was administered viatail vein injection, and at various time points (normally 5, 15, 30,60minutes and 2,4,6 and 24 hours) blood was withdrawn from the cannula Inmice, the test compound was also administered via tail vein injection,and at various time points. Blood was normally obtained by cardiacpuncture. The concentration of the remaining test compound wasdetermined by HPLC.

In general, the compounds of the invention were active in the above testin vivo and demonstrated a broad spectrum of activity.

Example 3 Determination of Tissue Accumulation

A. Tissue Distribution Using Radiolabeled Compound

This procedure is used to examine the tissue distribution, excretion andmetabolism of a radiolabeled test compound in both male and female ratsfollowing intravenous infusion at 10 mg/kg. Male and femaleSprague-Dawley rats (n=2 per sex per compound) are dosed with ³H-labeledtest compound at 10 (400 μCi/kg) and 12.5 mg/kg (100 μCi/kg),respectively, via intravenous infusion (˜2 min). The test compound isformulated in 5% hydroxypropyl-β-cyclodextrin as 2.5 mg/mL solution.Urine and feces are cage collected over 24 hours period. At 24 hoursafter dosing, animals are sacrificed and tissues are removed. Serum,urine and tissues are analyzed for total radioactivity by oxidationfollowed by liquid scintillation counting. Urine and selected tissuessamples are extracted and analyzed by reverse phase HPLC withradioactive flow detector for the presence of potential metabolites.

B. Tissue Accumulation Following Single Dose

This procedure is used to evaluate tissue distribution of a testcompound in rats following single dose administration by infusion. MaleSprague-Dawley rats (n=3 per dose groups) are dosed with 50 mg/kg of atest compound. Two formulations are used: 30% PEG 400 and 10%sulfobutylether-β-cyclodextrin. Urine samples are cage collected over 24hours. Blood samples are collected for serum chemistry and concentrationdetermination. Liver and kidneys are removed for histology evaluation.One kidney and part of the liver are homogenized for concentrationanalysis using reverse phase HPLC with UV detection. Drug concentrationsin urine and serum samples are determined by LC-MS analysis.

C. Tissue Distribution Following Multiple Doses

This procedure is used too evaluate the potential tissue accumulation ofa test compound in rats following multiple dose administration byintravenous infusion. Male and female Sprague-Dawley rats (n=4 per sexper dose group) are dosed with a test compound at 12.5, 25 and 50 mg/kgper day for seven days. Animals are sacrificed at day 1 (n=3 per sex perdose group) following the last dose administered. One animal per sex perdose group is retained as recovery animal and sacrificed at day 7following the last dose administered. The test compound is formulated in5% hydroxypropyl-β-cyclodextrin or 1% sucrose/4.5% dextrose. Urinesamples are cage collected at days 1 and 7 post-dose. Blood samples arecollected for serum chemistry and concentration determination. Liver andkidneys are removed for histology evaluation. One kidney and part of theliver are homogenized for concentration analysis using reverse phaseHPLC with UV detection. Drug concentrations in urine and serum samplesare determined by LC-MS analysis.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

1. A glycopeptide of formula II:

wherein: R³ is —OH; R⁵ is hydrogen; R¹⁹ is hydrogen; R²⁰ is—R^(a)—S—(CO)—R^(h); R^(a) is alkylene, alkenylene, alkynylene,cycloalkylene, cycloalkenylene arylene, heteroarylene, heterocyclene,—C(O)-alkylene, —C(O)-alkenylene —C(O)-alkynylene, —C(O)-cycloalkylene,—C(O)-cycloallcenylene —C(O)-arylene, —C(O)-heteroarylene orheterocyclene; and R^(h) is alkyl, alkenyl, alkynyl, cycloalkyl,cydoalkenyl, aryl, heteroaryl, or heterocyclic; or a pharmaceuticallyacceptable salt, stereoisonier, or prodrug thereof.
 2. The glycopeptideof claim 1, wherein R^(a) is alkylene, alkenylene, alkynylene,—C(O)-alkylene, —C(O)-alkenylene, or —C(O)-alkynylene, and R^(h) isalkyl, alkenyl, or alkynyl.
 3. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim
 1. 4. The pharmaceutical composition ofclaim 3, where the composition further comprises a cyclodextrin.
 5. Theglycopeptide of claim 1, wherein R^(a) is alkylene.
 6. The glycopeptideof claim 1, wherein R^(h) is alkyl.
 7. A method of treating a mammalhaving a bacterial disease, the method comprising administering to themammal a therapeutically effective amount of a glycopeptide of claim 1,thereby effectively treating the bacterial disease.
 8. A method oftreating a mammal having a bacterial disease, the method comprisingadministering to the mammal a therapeutically effective amount of apharmaceutical composition of claim 3, thereby effectively treating thebacterial disease.